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In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas.

Abstract
Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x(L), and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Emu-myc transgenic mice or Emu-myc mice that also expressed an Emu-bcl-2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc/bcl-2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc/bcl-2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.
AuthorsKylie D Mason, Cassandra J Vandenberg, Clare L Scott, Andrew H Wei, Suzanne Cory, David C S Huang, Andrew W Roberts
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 46 Pg. 17961-6 (Nov 18 2008) ISSN: 1091-6490 [Electronic] United States
PMID19004807 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • ABT-737
  • Biphenyl Compounds
  • Mutagens
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Sulfonamides
  • Cyclophosphamide
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Biphenyl Compounds (pharmacology, therapeutic use)
  • Cyclophosphamide (therapeutic use)
  • Disease-Free Survival
  • Lymphoma (drug therapy, pathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutagens (toxicity)
  • Nitrophenols (pharmacology, therapeutic use)
  • Piperazines (pharmacology, therapeutic use)
  • Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
  • Proto-Oncogene Proteins c-myc (metabolism)
  • Sulfonamides (pharmacology, therapeutic use)
  • Time Factors
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

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